The goal of this competitive renewal application is to define those mechanisms that account for PA's effects on mammary carcinogenesis and that are dependent on PA intensity and duration, and independent of differences in body weight. Three specific aims are proposed:1) How does PA intensity inhibit the carcinogenic process? A range of PA intensities will be investigated to test the linearity of the carcinogenic response. This will permit evaluation of the hypothesis that PA, in proportion to its intensity, inhibits mammary carcinogenesis by suppressing mTOR activation. Experiments are also proposed to determine if PA suppresses mTOR via its effect on circulating levels of insulin-like growth factor-1 (IGF-1); 2) How does increasing PA duration diminish cancer inhibitory activity? Our data clearly indicate that cancer inhibitory activity decreases with increasing PA duration. The non linear (J or U-shaped) carcinogenic response to PA duration is referred to as hormesis, a physiological cellular stress response. The objective of this aim is to identify the target signaling pathway accounting for the hormetic response and the connection between PA and that pathway. If mTOR-IGF-1 is not explanatory, alternative hypothesis centers on sirtuins and forkhead transcription factors (FOXO) by IL-6;and 3) How does PA affect the expansion of tumor mass in mammary carcinomas? After mammary tumors reach a measurable size, PA will be initiated with the objective of identifying subcategories of tumors (initially categorized by estrogen and progesterone receptor status and Her-2/Neu expression) that regress in response to PA; mechanisms that account for regression will be identified. Our hypothesis is that PA limits the amount of energy substrates reaching mammary carcinomas thereby inducing apoptosis by reversing tumor-associated metabolic reprogramming. The proposed pre-clinical experiments have the potential to facilitate the translation of pre-clinical and clinical research to public health recommendations for PA directed to cancer prevention and control.